A method of processing liquids using electric fields is described in, for example, GB-A-1569707. In this method, which is known as the electrohydrodynamic method (sometimes also referred to herein as “EHD”), liquid issuing from an outlet is subjected to an electric field such that the net electrical charge in the liquid as the liquid emerges into free space or air counteracts the surface tension forces of the liquid and the repulsive forces generated by the like electrical charges result in a cone and jet. Depending upon the liquid formulation, the liquid jet may then, as described in GB-A-1569707, breakup into liquid droplets, or may, as described in, for example, the applicant's WO 98/03267 (the whole contents of which are incorporated by reference), break up to form solid or gel-like particles or may form a continuous fibre which may break-up into short lengths (“fibrils”). The products resulting from the electrodynamic method are, for convenience, collectively referred to herein as “electrosols”.
This electrohydrodynamic method is particularly good at controlling the dimensions of the resultant product and provides an extremely efficient way of delivering drugs or medicaments to the respiratory system, for example to the pulmonary system, and to other epithelial or topical surfaces such as wound surfaces as described in WO 98/03267. Furthermore, as described in WO 98/03267 electrohydrodynamic methods may be used to spray complex colloids, provided the colloid is initially in a substantially liquid form.
The electrohydrodynamic method enables sprays or clouds of droplets (“aerosols”) to be produced in which the droplets are monodispersed, that is they have a very uniform size and does not, unlike some conventional aerosol producing methods, require a propellant gas. This makes inhalers using the electrohydrodynamic method such as described in the applicant's U.S. Pat. No. 4,962,885, U.S. Pat. No. 6,105,877, U.S. Pat. No. 6,105,571, U.S. Pat. No. 5,813,614, U.S. Pat. No. 5,915,377 and WO 99/07478 (which enable delivery of at least partially electrically discharged droplets) and WO 00/35524 (which enables delivery of electrically charged droplets) particularly advantageous because the absence of a gas propellant makes the inhaler easy to use as inhalation does not have to be timed with the expulsion of gas from the inhaler and the monodispersed nature of the aerosol combined with the ability provided by the electrohydrodynamic method to control the size of the droplets enables drugs or other medicaments to be targeted to a particular region of the respiratory system, for example a specific region of the lung. The whole contents of U.S. Pat. No. 4,962,885, U.S. Pat. No. 6,105,877, U.S. Pat. No. 6,105,571, U.S. Pat. No. 5,813,614, U.S. Pat. No. 5,915,377, WO 99/07478, and WO 00/35524 are hereby incorporated by reference.
As more is understood about the way biological species operate, veterinary and medical treatments increasingly incorporate biological molecules or material such as DNA, RNA, proteins, peptides, hormones, lipids, cytokines, etc. into therapies, treatments and prophylactic medicaments such as vaccines. As used herein the term “biological material” includes biological molecules, biological molecule fragments such as DNA fragments and recombinant biomolecules, including proteins such as enzymes and other biological material of a similar size. These biological materials vary in their complexity but some, particularly proteins and DNA, are extremely sensitive to their immediate surroundings and can easily be broken down or denatured which can reduce their activity and even eliminate it altogether. The delivery of biological material also requires the occasional use of isotonic or buffered liquid vehicles, and because such materials are often expensive to produce, delivery systems must be as efficient as possible.
Traditional methods of atomising liquids of this kind, such as air-jet or ultrasonic nebulization, impart large shear forces on the carrier liquid and hence also on the biological material inside. Shear forces of this magnitude are known to denature sensitive biological materials such as DNA or proteins and thus there is no readily available delivery method that is immediately suitable for therapies that use such biological materials.
The carrier liquids for the biological material mentioned above are generally aqueous and relatively highly conductive. Unfortunately, EHD is well known to have difficulty in spraying conductive liquids. Numerous patents and published papers indicate that the resistivity of the liquid to be sprayed must be above 10,000 Ohm.m. Liquids below this will spray, but there seems to be a cut-off at around 100 Ohm.m, below which no aqueous-based formulation will spray in air. This is partly due to the surface tension of water which is high, approximately 72 mN/m (milli Newtons per metre), and partly due to the polar nature of water, which makes any impurities such as a water soluble drug contribute significantly to the liquid conductivity. This has meant that non-aqueous solvents such as ethanol tend to be used for EHD.
Furthermore, EHD comminution uses high voltages (1 KV and above) to break up liquid formulations by direct counteraction of the surface tension of the liquid. The use of such high voltages raises several potential practical problems, namely: 1) that the electric field might directly influence, denature or break up delicate, for example biological, materials in the liquid; 2) that breaking up the bulk liquid into small droplets might physically denature such delicate biological materials through excessive shear forces; and 3) that air which breaks down around the nozzle might create ozone which will react with any water in the formulation to produce hydrogen peroxide which is itself a strong oxidant and the presence of which could lead to molecular denaturation.
These problems have meant that EHD has to date only really been practical for small, robust molecules, such as salbutamol and budesonide, which have good solubility in alternative solvents like ethanol. However, ethanol is not a good solvent for biological materials because it can cause precipitation (as it does for DNA) and denaturation (as it does for delicate proteins).